Integrins are a family of transmembrane receptors, each of which is composed of a pair of heterodimeric, noncovalently associated glycoproteins, designated as α and β chains. The α subunit contains heavy and light chains as part of its extracellular domain, with 3-4 divalent-cation binding sites; the light chain also contains transmembrane and intracellular domains. The β-subunit contains a large extracellular domain, as well as transmembrane and intracellular domains. Integrins are cell surface receptors, which bind to extracellular matrix adhesive proteins such as fibrinogen, fibronectin, vitronectin and osteopontin. These transmembrane glycoproteins are classified by the β subunits. The β3 class of integrin family has received the most attention in recent drug discovery efforts (W. J. Hoekstra, Current Medicinal Chemistry, 1998, 5, 195), however, the β5 class has also become a focus of attention. Some of the disease states that have been associated with a strong β3 and β5 integrin component in their etiologies are thrombosis (integrin α2bβ3 also called GPIIb/IIIa); unstable angina (GPIIb/IIIa); restenosis (GPIIb/IIIa and integrin αvβ3); arthritis, vascular disorders or osteoporosis (αvβ3); tumor angiogenesis, multiple sclerosis, neurological disorders, asthma, vascular injury or diabetic retinopathy (αvβ3 or αvβ5) and tumor metastasis (αvβ3). See S. A. Mousa, et al., Emerging Therapeutic Targets, 2000, 4(2) 148-149; and W. H. Miller, et al., Drug Discovery Today, 2000, 5(9), 397-40. Antibodies and/or low-molecular weight compound antagonists of αvβ3 have shown efficacy against these respective disease states in animal models (J. Samanen, Current Pharmaceutical Design, 1997, 3 545-584) and thereby offer promise as therapeutic agents. Several patents have described compounds that could interact with these integrins. For example, U.S. Pat. No. 5,919,792 B1, U.S. Pat. No. 6,211,191 B1, and WO 01/96334 and WO 01/23376 describe αvβ3 and αvβ5 integrin receptor antagonists.
The present invention provides a new class of piperidinyl compounds, which selective bind to β3, β5 or dual integrin receptors (e.g. αvβ3 and αvβ5) for the treatment of a wide variety of integrin mediated disease states.